Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This invention relates to a process for preparing an epimer of a 7a-malonamido-7a-methoxy-3-tetrazolyl-thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid ester represented by the formula (I) which comprises epimerizing the other corresponding epimer represented by the formula (II) with a base selected from the group consisting of alklai metal hydrogen carbonate, tri-lower alkylamine, diethanolamine, triethanolamine pyridine, picoline, lutidine and collidine and then precipitating the product: wherein
• the hydroxyphenyl group in substituent Ar can be optionally protected.
• the protecting group can be, -for example, alkanoyl, methoxyethyl, tetrahydropyranyl, p-methoxybenzyl, t-butyl or the like.
• the carboxy protecting group B l or B 2 is well known in the field of penicillin or cephalosporin chemistry as capable of being introduced or removed under conditions not affecting other parts of the molecule.
• Such a protective group can be one forming an optionally substituted aliphatic ester, e.g., t-butyl, trichloroethyl, allyl or the like ester, especially 1-oxyalkyl ester as 1-alkanoyloxyalkyl ester, e.g., acetoxymethyl, pivaloyloxymethyl or the like ester, 1-alkoxyformyloxyalkyl ester, e.g., ethoxycarbonyloxyethyl or like ester, 1-alkoxyaliphatic ester, e.g., methoxymethyl, tetrahydropyranyl, 2-oxo-1,3-dioxolenylmethyl or like ester, aralkyl ester, e.g., benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl
• the protective group is usually absent in the desired antibacterial compound which can be prepared from the intermediates of this invention.
• the structure of the protective group in itself has less importance so long as the objective carboxy protection is satisfactory, is accompanied by fewer side reactions and does not affect the course of the reaction.
• B 1 and/or B 2 each is a hydrogen or alkali metal atom, e.g., latamoxef or its salt, i.e., B 1 and B 2 are hydrogen or sodium, Ar is hydroxyphenyl and Tet is 1-methyl-1 H-tetrazol-5-yl or its derivatives.
• the present inventors sought a method for separating these epimers on an industrial scale and found that when a compound represented by the formula (II) is dissolved in ethyl acetate and concentrated in the presence of pyridine, over 80% of the epimer (II) is isomerized to the corresponding epimer (I) and then crystallizes as the pure epimer (I).
• the inventors have completed the invention on the basis of this discovery.
• latamoxef or a closely related antibacterial has higher antibacterial activity when it is the (R)-epimer (II) rather than the (S)-epimer (I).
• the compound (I) of this invention epimerizes from its (S)- to the antibacterially favourable (R)-configuration during the reactions and treatment for the preparation of the end product latamoxef (II) in which 8 1 and 8 2 are hydrogen.
• the compound of this invention is the stereochemically reverse epimer of the active latamoxef does not cause any difficulties for the final preparation of the latter.
• the process of this invention is carried out by dissolving a compound represented by the formula (II) in a solvent mixed with a base, and then precipitating the epimer by letting it stand for a while, by diluting with a sparingly dissolving solvent or by concentrating.
• the precipitate may not always be in a crystalline form.
• the solvent can be water or an organic solvent, e.g., an industrial organic solvent belonging to a series of hydrocarbons, e.g., pentane, hexane, oxtane, benzene, toluene or xylene; halohydrocarbon, e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane or chlorobenzene; ether, e.g., diethyl ether, methyl isopropyl ether, dioxane or tetrahydrofuran; ketone, e.g., acetone, methyl ethyl ketone or cyclohexanone; ester, e.g., ethyl acetate, isobutyl acetate, methyl benzoate or isopropyl benzoate; nitrohydrocarbon, e.g., nitro
• dimethyl sulfoxide orthiane-1,1-dioxide dimethyl sulfoxide orthiane-1,1-dioxide
• organic base e.g., diethylamine, triethylamine, diethanolamine, pyridine, picoline, collidine or quinoline
• alcohol e.g., methanol, ethanol, propanol, hexanol, octanol or benzyl alcohol
• an industrial solvent belonging to other series of solvents or mixtures of two or more of the above cited solvents Especially preferable is a hydrocarbon, halohydrocarbon, ester, ketone, ether, alcohol, amide or sulfoxide solvent or water.
• the amount of the base to be added can be from 100 ppm to several percent.
• the amount of the added solvent is usually at least the amount which is capable of dissolving the starting material.
• the reaction temperature usually ranges from -50°C to 100°C.
• the sparingly dissolving solvent can be one selected from the above mentioned solvents in which the objective compound (I) has a low solubility.
• vacuum evaporation is usually employed. When the product is amorphous, the concentrating rate is carefully controlled so as to avoid separation of the unreacted starting epimer (II).
• the product of this invention is useful as starting material for synthesizing antibacterial (3-lactams.
• the resultant material is purified by silica gel chromatography to give the corresponding bis-diphenylmethyl ester (8.5 g) from the fractions eluted with a benzene-ethyl acetate (2:1) mixture.
• This product is a mixture (1:1) of the (R)- and (S)-epimers at the a-position of the side chain attached to the 7-position.
• the product contains 2 molar equivalents of crystal ethyl acetate. mp. 119-122°C.
• This product contains 1.5 molar equivalent of crystal benzene; mp. 119-122°C.
• the same product can be prepared by treating the same starting material in the form of a disodium salt with a molar equivalent amount of p-nitrobenzyl bromide in N,N-dimethylacetamide for 1.5 hours, and then crystallizing the product from dichloromethane containing 0.1% quinoline; mp. 120-123°C.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (2)

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Families Citing this family (29)

Family Cites Families (8)

• 1982
  • 1982-07-02 JP JP57116048A patent/JPS597193A/ja active Granted
• 1983
  • 1983-06-14 US US06/504,287 patent/US4504658A/en not_active Expired - Lifetime
  • 1983-06-17 NZ NZ204627A patent/NZ204627A/en unknown
  • 1983-06-20 ZA ZA834495A patent/ZA834495B/xx unknown
  • 1983-06-20 GR GR71721A patent/GR78620B/el unknown
  • 1983-06-28 CA CA000431350A patent/CA1192193A/en not_active Expired
  • 1983-06-29 IE IE1527/83A patent/IE55767B1/en not_active IP Right Cessation
  • 1983-06-29 RO RO111456A patent/RO86355B/ro unknown
  • 1983-06-29 GB GB08317634A patent/GB2124217B/en not_active Expired
  • 1983-06-30 PH PH29144A patent/PH21139A/en unknown
  • 1983-06-30 FI FI832407A patent/FI832407L/fi not_active Application Discontinuation
  • 1983-06-30 HU HU832380A patent/HU187944B/hu not_active IP Right Cessation
  • 1983-06-30 KR KR1019830002960A patent/KR890000812B1/ko not_active IP Right Cessation
  • 1983-06-30 NO NO832387A patent/NO832387L/no unknown
  • 1983-06-30 AR AR83293493A patent/AR242391A1/es active
  • 1983-06-30 BG BG8361551A patent/BG37526A3/xx unknown
  • 1983-07-01 DE DE8383106437T patent/DE3363161D1/de not_active Expired
  • 1983-07-01 DE DE198383106437T patent/DE98545T1/de active Pending
  • 1983-07-01 DD DD83252667A patent/DD210052A5/de unknown
  • 1983-07-01 AT AT83106437T patent/ATE19401T1/de not_active IP Right Cessation
  • 1983-07-01 SU SU833613971A patent/SU1225488A3/ru active
  • 1983-07-01 YU YU1445/83A patent/YU44011B/xx unknown
  • 1983-07-01 ES ES523774A patent/ES523774A0/es active Granted
  • 1983-07-01 PL PL1983242776A patent/PL141782B1/pl unknown
  • 1983-07-01 AU AU16496/83A patent/AU564850B2/en not_active Ceased
  • 1983-07-01 DK DK304983A patent/DK160502C/da not_active IP Right Cessation
  • 1983-07-01 EP EP83106437A patent/EP0098545B1/en not_active Expired
  • 1983-07-01 PT PT76973A patent/PT76973B/pt unknown
  • 1983-07-02 EG EG406/83A patent/EG16539A/xx active
  • 1983-07-03 IL IL69146A patent/IL69146A/xx not_active IP Right Cessation
  • 1983-07-04 CS CS835036A patent/CS244940B2/cs unknown

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